Peroxisome Proliferator-Activated Receptors as Molecular Links between Caloric Restriction and Circadian Rhythm

Abstract

The circadian rhythm plays a chief role in the adaptation of all bodily processes to internal and environmental changes on the daily basis. Next to light/dark phases, feeding patterns constitute the most essential element entraining daily oscillations, and therefore, timely and appropriate restrictive diets have a great capacity to restore the circadian rhythm. One of the restrictive nutritional approaches, caloric restriction (CR) achieves stunning results in extending health span and life span via coordinated changes in multiple biological functions from the molecular, cellular, to the whole-body levels. The main molecular pathways affected by CR include mTOR, insulin signaling, AMPK, and sirtuins. Members of the family of nuclear receptors, the three peroxisome proliferator-activated receptors (PPARs), PPARα, PPARβ/δ, and PPARγ take part in the modulation of these pathways. In this non-systematic review, we describe the molecular interconnection between circadian rhythm, CR-associated pathways, and PPARs. Further, we identify a link between circadian rhythm and the outcomes of CR on the whole-body level including oxidative stress, inflammation, and aging. Since PPARs contribute to many changes triggered by CR, we discuss the potential involvement of PPARs in bridging CR and circadian rhythm.

Keywords: caloric restriction; circadian rhythm; metabolism; nuclear receptors.

Figure 1

Transcription feedback loops driving circadian rhythm. CLOCK and BMAL1 heterodimers initiate expression of PERs, CRYs, REV–ERBα, and RORs by binding to the E–box element. PER and CRY heterodimers inactivate CLOCK and BMAL1. REV–ERBα and RORs activate or inhibit, respectively, the expression of ROR response element (RORE) containing genes including Cry and Bmal1. Abbreviations: BMAL1—brain and muscle ARNT–like protein 1; CLOCK—circadian locomotor output cycles kaput; CRY—cryptochrome; PER—period, ROR—retinoic acid–related orphan receptor.

Figure 2

Circadian rhythm affects the main molecular pathways mediating the outcome of caloric restriction (CR). Various types of interactions connect the CR–associated pathways mTOR, insulin signaling, AMPK, and sirtuins with circadian rhythm. Abbreviations: AMPK—adenosine monophosphate (AMP) activated protein kinase; CKIε—casein kinase ε; CLOCK—circadian locomotor output cycles kaput; Dec1—differentially expressed In chondrocytes 1; IGF–1—insulin–like growth factor 1; IRS—insulin receptor substrates; LKB1—liver kinase B1; mTOR—mammalian target of rapamycin; NAD—nicotinamide adenine dinucleotide; NAMPT—nicotinamide phosphoribosyltransferase; SIRT1—Sirtuin 1; SCN—suprachiasmatic nucleus, S6K1—ribosomal protein S6 kinase 1. The circled Ac indicates acetylation and circled P phosphorylation.

Figure 3

The role of PPARs in circadian rhythm. The levels of all PPARs are regulated according to daily oscillations. PPARα targets the expression of lipid metabolism–related genes resulting in rhythmic changes in the levels of triacylglycerols (TAG). PPARα interacts directly with PER2 to modulate gene expression. In the muscle, PPARβ/δ regulates the expression of lipogenic genes in a rhythmic manner. PPARβ/δ is also an indirect target of the circadian clock via miR–122. PPARγ regulates expression of core circadian genes including Bmal1 and Rev–erbα, which support adipogenesis. In the liver, PPARγ also mediates the action of circadian triggers derived from gut microbiota in response to high–fat diet (HFD). PPARs bind to PPRE as PPAR:RXR heterodimers. Abbreviations: Acc—acetyl–CoA carboxylase; Fas—fatty acid synthase; Hmg–CoAR—β–hydroxy β–methylglutaryl–CoA reductase; PGC–1α—peroxisome proliferator–activated receptor γ coactivator 1 α; PPRE—PPAR response element; RXR—retinoid X receptor; Scd–1—stearoyl–CoA desaturase–1; Srebp—sterol regulatory element–binding protein 1.

Figure 4

PPARs contribute to the processes regulated by CR and circadian rhythm at the whole–body level. CR exerts its beneficial effects by reducing oxidative stress, delaying aging, and inhibiting inflammation. Circadian rhythm affects all of these processes. PPARs regulate the expression of antioxidative enzymes, inflammatory cytokines, and metabolic processes. For the effects of SIRT refer to Figure 2. Abbreviations: AP–1—activating protein–1; CAT—catalase; COX–2—cyclooxygenase–2; eNOS—endothelial NO synthase; GPx—GSH peroxidase; GR—GSH reductase; GSH—glutathione; GSSG—oxidized glutathione; GST—GSH S–transferase; iNOS—inducible NO synthase; NRF2—nuclear factor erythroid 2–related factor 2; PRX—peroxiredoxins; ROS—reactive oxygen species; SOD—superoxide dismutase; STAT1—signal transducer and activator of transcription 1.